Process for rearranging 6-acylamidopenicillanic acid-1-oxides to 7-acyla mido-3-methyl-ceph-3-em-4-carboxylic acids

ABSTRACT

6-Acylamidopenicillanic acid-1-oxides can unexpectedly be directly rearranged to 7-acylamido-3-methylceph-3-em-4-carboxylic acid without the necessity of first esterifying the 3-carboxyl function of the penicillin. For example, the rearrangement can be affected by treating 6-phenoxyacetamidopenicillanic acid sulfoxide with pyridine-di(phosphoric acid) complex (salt) to produce 7-phenoxy-acetamido-3-methylceph-3-em-4-carboxylic acid in 36 percent yield.

United States Patent [191 lltniointeld et al.

[451 Oct. 22, 1974 [5 PROCESS FOR REARRANGING fi-ACYLAMIDOPENICILLANICACID-l-OXIDES TO 7-ACYLA MIDO-3-METHYL-CEPH-3-EM-4- cnn goxyuc Acrps[75] Inventors: Joseph Rubinfeld, Northport, N.Y.;

Raymond Urgel Lemiuex; Rintje Raap, both of Edmonton, Alberta,

Canada H V l [73] Assignee: Bristol-Myers Company, New York,

[22] Filed: May 11, 1971 [21] Appl. N0.: 143,683

[52] US. Cl. 260/243 C, 260/2391 [51] Int. Cl C07d 99/24 [58] Field ofSearch 260/243 C [56] References Cited UNITED STATES PATENTS 3,275.6-69/1966 Morin et a1. 260/243 C 3,668, 01 6/1972 Gutowski 260/243 C 6/1972Foster et a1. 260/243 C 3,725,397 4/1973 Graham et a1. 260/243 C3,725,399 4/1973 Ellerton et al. 260/243 C FOREIGN PATENTS ORAPPLICATIONS 70/1627 2/1970 South Africa OTHER PUBLICATIONS Abstracts ofACS 160th National Meeting, Sept. l4-17, (1970), Division of MedicinalChemistry.

Primary Examiner Nicholas S. Rizzo Attorney, Agent, or Firm-Robert E.Havranek [5 7] ABSTRACT 6-Acylamidopenicillanic acid-l-oxides canunexpectedly be directly rearranged to 7-acylamido-3-methylceph-3-em-4-carb0xylic acid without the neces sity of firstesterifying the 3-carboxyl function of the penicillin. For example, therearrangement can be al fected by treating6-phen0xyacetamidopenicillanic acid sulfoxide withpyridine-di(phosphoric acid) complex (salt) to produce7-phenoxy-acetamido-3- methylceph-3-em-4-carb0xylic acid in 36 percentyield.

1 Claim, N0 Drawings .1 PROCESS FOR REARRANGING 6-ACYLAMIDOPENICILLANICACID-l-OXIDES TO 7-ACYLA MIDO-3-METHYL-CEPH-3-EM-4- CARBOXYLIC ACIDSBACKGROUND OF THE INVENTION 1. Field of the Invention Due to the everincreasing importance of the cephalosporin antibiotics in medicine, ithas become highly important to develop new and better methods of producing the cephalosporin nucleus, 7-ACA and 7 ADCA(7-aminocephalosporanic acid and 7- aminodeacetoxycephalosporanic acid)in good yields. The present invention is directed to that effort.

2. Description of the Prior Art Thisinvention is directed to thepreparation of 7- acylamido-3-methylceph-3-em-4-carboxylic acids by thesulfoxide rearrangement of corresponding 6- acylamidopenicillanicacid-l-oxides. There is much art in the literature relating to therearrangement of penicillin-l-oxide esters to the corresponding 3-methylceph-3-em-4-carboxylate esters but all of this art teaches thenecessity of the 3-carboxyl function of the penicillin being in the formof a carboxylic ester lest decarboxylation occur. The most pertinent artfound is:

A. US. Pat. No. 3,275,626, issued Sept. 27, 1966 to Morin and Jackson.This patent teaches the rearrangement of 6B-acylamidopenicillanic acidester.

cillin Sulfoxide, A synthesis of Cephalosporin Compound, J. Am. Chem.Soc., 9l, 1401 (Mar. 12, 1969). It was unequivocally stated in thispublication that The only product which could be isolated andcharacterized from the acetic anhydride and acid-catalyzed rearrangementof penicillin sulfoxide free acids was3-methyl-7-(2-phenoxyacetamido)-3-cephem."

4. Morin, Jackson et al., report in J. Am. Chem. Soc. 85, I896 (June 20,1963) that the rearrangement of penicillin sulfoxide acid results indecarboxylation.

5. South African Pat. No. 68/2780 to Eli Lilly and Company clearlystates that "In all cases, they (the prior art penicillins) must beesterified and con verted into the corresponding sulfoxide prior totreatment, i.e., rearranged to 3-methyl-3-cephem- 4-carboxylatederivative.

6. US. Pat. No. 3,l'97,466, issued July 27, 1965, to Chow et al. Thispatent teaches the preparation of penicillin sulfoxides.

7. Suddal, Morch and Tybring teach the preparation of penicillinsulfoxides in their article entitled Penicillin Oxides, TetrahedronLetters, 9, p. 381 (1962).

8. South African Pat. No. 68/5889 to Eli Lilly and Company describes aprocess for the preparation of penicillin sulfoxide esters.

9. South African Pat. No. 70/ 1627 to Glaxo Laboratories Limiteddescribes the rearrangement of penicillin sulfoxide esters into3--methylceph-3-em-4- carboxylic acid esters using acid-amine complexeswith the aid of heat. No teaching is found therein that compounds otherthan penicillin sulfoxide esters can be rearranged without thedecarboxylation of the carboxyl group. All the examples shown thereinand the claims thereto are directed to the rearrangement of penicillanicacid sulfoxide esters into 3-methylceph-3-em-4-carboxylate esters.

SUMMARY OF THE INVENTION This invention relates to a new and efficientprocess for the preparation of 7-acylamido-3methylceph-3-em-4-carboxylic acids having the formula ll H R-C-N----( CP 0 N whereinR is the side chain of a penicillin produced by fermentation, and M is Hor a cation, said process comprising the rearrangement of the compoundhaving the formula This invention relates to a new and unexpectedlysuccessful process for the preparation of 7-acylamido-3-methylceph-3-em-4-carboxylic acids of the formula -iH S R-C-N amples inwhich R is the side chain ofa penicillin produced by fermentation, from6-acylamidopenicillanic acid sulfoxides having the formula in which R isas above, and M is H or a cation, by the treatment of said penicillanicacid sulfoxide with a strong acid and a nitrogen base, with the aid ofheat.

For the purpose of this disclosure, the term cation is meant to includethose metallic cations such as sodium, potassium, calcium, aluminum,lithium and the like, and organic amine cations such as trialkylamines,e.g., triethylamine, trimethylamine, dibenzylamine,N-benzyl-B-phenethylamine, N-(lower)alkylpiperidines, e.g.,N-ethylpiperidine, pyridine, and other amines which have been used toform salts with benzylpenicillin or the like.

The term penicillin produced by fermentation is meant to include allthose penicillins known in the art to be prepared by a fermentationprocess according to Behrens Rule [Medicinal Chemistry, 3rd Edition, p.382, A. Burger, Wiley-lnterscience (Pub.)] and most particularly includethose penicillins having the forwherein R is phenyl, benzyl,phenoxymethyl, phenylmercaptomethyl, such phenyl, benzyl, phenoxymethyl,and phenylmercaptomethyl substituted with chlorine, methyl, methoxy, ornitro groups, as well as heptyl, and

thiophene-Z-methyl. Penicillins with these representative R groups arethe more economically prepared or more readily obtainable byfermentation methods. Exof such penicillins and the 7-acylamidodesacetoxycephalosporanic acids which are obtained therefromafter sulfoxide formation and heat rearrangement by the above-referencedmethods include:

Benzyl penicillin to form 7- (phenylacetamido)desacetoxycephalosporanicacid;

Phenoxymethyl penicillin to form 7- 3,4-Dimethoxybenzyl penicillin toform 7-(3,4- dimethoxyphenylacetamido)desacetoxycephalosporanic acid;

4-Methoxyphenoxymethyl penicillin to form 7-(4-methoxyphenoxyacetamido)desacetoxycephalosporanic acid;

4-Methylbenzyl penicillin to form 7-(4-methylphenylacetamido)-desacetoxycephalosporanic acid;

4-Nitrophenoxymethyl penicillin to form 7-[2-(4-nitrophenoxy)-acetamido]desacetoxycephalosporanic acid; and

3,5-Dimethylphenylmercaptomethyl penicillin to form7-[2-3,5"-dimethylphenylmercapto)-aceta- L .9] l9a9qLQ1yP, sp ni a i Theinvention is thus principally concerned with the conversion of6-acylamidopenicillanic acid-l-oxides into7-acylamido-3-methylceph-3-em-4-carboxylic acids.

In US. Pat. No. 3,275,626 there is described a general method ofpreparing antibiotic substances, including cephalosporins, whichcomprises heating a socalled penicillin sulphoxide exter, under acidconditions, to a temperature of from about to about C.

- In South African Pat. No. 70/ 1627 there is described a general methodof preparing 3-methylceph-3-em-4- carboxylate esters which comprisesheating a so-called penicillin sulfoxide ester with a salt comprised ofa nitrogen base and an acid. Both of the prior art patents teach thenecessity of conducting the rearrangement on penicillin sulfoxide esterslest decarboxylation occur in the resulting ceph product.

It is an object of the invention to provide a novel process for therearrangement of penicillin sulfoxide acid compounds to cephalosporinacid compounds. We have found that the rearrangement can be affected ingood yields by means of certain catalytic systems.

In many instances the process can be effected with ease and economy ofoperation. The rearrangement is best performed under catalytic acidconditions using preferably polybasic acids such as ortho phosphoricacid, partially neutralized by basic solvents and more preferably by theaddition of small amounts of a weakly basic substance such as pyridineor quinoline. For convenience we have described these catalysts as beingcomplexes or salts although it should be understood that the termcomplex" is interchangeable with salts. Moreover, under the conditionsof the reaction the salt or complex may exist in a dissociated form.

According to an embodiment of the present invention therefore there isprovided a process for the preparation of7-acylamido-3-methylceph-3-em-4-carboxylic acid comprising rearranging a6-acylamidopenicillanic acid-l-oxide in a weakly basic organic solvent,such as dioxane or diglyme, in the presence of a nitrogen base having apKb of not less than 4, and an acid, which will form salts or complexes,which salt may be formed in situ in the reaction mixture. The acidshould preferably be a polybasic, for example, an organic acid such as aphosphonic or phosphoric acid.

The phosphorous containing acid may be orthophosphoric, polyphosphoric,pyrophosphoric or phosphorous acid or it may be a phosphonic acid. Thephosphonic acid may be an aliphatic, araliphatic or aryl phosphonicacid; the aliphatic, araliphatic or aryl group of such a phosphonic acidmay be a hydrocarbon group (e.g., a lower alkyl, phenyl lower alkyl orphenyl group) or a hydrocarbon group substituted by, for example, ahalogen atom or a nitro group. Examples of aliphatic phosphonic acidsinclude the lower alkyl and substituted (e.g., halogeno) lower alkylphosphonic acids such as methane phosphonic acid, ethane phosphonicacid,clichloromethane phosphonic acid, trichloromethane phosphonic acidand iodomethane phosphonic acid. Examples of aryl phosphonic acidsinclude the benzene and substituted (e.g., halogeno or nitro) benzenephosphonic acids, e.g., bromobenzene phosphonic acids andnitro-benzenephosphonic acids.

The expression nitrogen base" is used herein as a convenient expressionfor a basic substance containing nitrogen although it may include otherhetero atoms, e.g., oxygen. We prefer, however, to use weakly basicorganic amines. Bases which may be used have a pKb for protonation ofnot less than 4 (i.e., as measured in water at 25 C.). The base may be apolyfunctional base having a nitrogen function with such a pKb for thefirst protonation step. The bases preferably have a pKb in water of notless than 7.

The organic base may be primary, secondary or tertiary; however, weprefer to employ weak tertiary organic bases. Illustrative of suchtertiary organic bases are the unsaturated heterocyclic bases such aspyridine, quinoline, isoquinoline benzimidazole and homologues thereof,for example the alkyl substituted pyridines and quinolines such as a-,B- and y-picolines and 2- and 4- methylquinolines. Other substitutedheterocyclic bases which may be used include those substituted byhalogen (e.g., chlorine or bromine), acyl (e.g., formyl or acetyl),acylamido (e.g., acetamido), cyano, carboxy, aldoximino and the like.

Other organic bases which may be used include aniline and nuclearsubstituted anilines such as halogeno anilines (e.g., o-chloroaniline,m-chloroaniline and pchloroaniline); anilines (e.g., o-methylaniline andmmethylaniline); hydroxyand (lower)alkoxyanilines (e.g.,o-methoxyaniline and m-hydroxy-aniline); nitroanilines (e.g.,m-nitroaniline) and carboxyanilines (e.g., m-carboxyaniline) as well asN-(lower)alkyl anilines (e.g., N-methylaniline) and N,N-di(lower)alkylanilines.

Preferred classes of catalytic systems are those obtained by thereaction of a phosphorus containing acid with a nitrogen base.Advantageous results have been obtained in the process according to theinvention when salts of orthophosphoric are employed as catalysts.However, equally advantageous results are obtained when the catalyst isgenerated in situ. Catalyst systems are obtained by reactingsubstantially molar equivalents of an acid with an aromatic heterocyclictertiary organic nitrogen base in a weakly basic solvent system.Advantageous results have been obtained in the process according to theinvention when complexes of pyridine, quinoline, isoquinoline orderivatives thereof substituted with lower alkyl, halogen, acyl,acylamido, cyano, carboxy, or aldoximino, are employed as catalysts.

Particularly preferred complexes of nitrogen bases are those obtained byreaction of a phosphorus containing acid with an aromatic heterocyclic,tertiary organic nitrogen base. Advantageous results have been obtainedin the process according to the invention when salts of orthophosphoricor a phosphonic acid with pyridine, quinoline, isoquinoline, or suchbases substituted by, for example, lower alkyl, halogen, acyl,acylamido, cyano, carboxy, or aldoximino are employed. Thus usefulcatalysts include pyridine; 2- methyl and 4-methyl-pyridine; quinolineand isoquinoline salts of orthophosphoric, methane phosphonic, ethanephosphonic, iodomethane phosphonic, dichloromethane phosphonic,trichloromethane phosphonic,

bromobenzene phosphonic and nitrobenzene phosphonic acids.

The catalytic system used in the process according to the invention maybe derived from proportions of the acid and the base such that one ormore of the acid function(s) are partially neutralized by the base andsolvent. Generally, a less than molar quantity of nitrogen base isemployed so that, in addition to the salt, the catalyst also comprisessome free acid.

The optimal ratio of acid: base catalytic system will depend on variousfactors including the nature of the acid and the base as well as thenature of the penicillanic acid sulfoxide. The optimal ratio may beascertained by preliminary trial and experiment.

One preferred catalytic system for use in the process according to theinvention is that obtained by the reaction of 1 mole of pyridine and 2moles of orthophosphoric acid in dioxane.

Another preferred catalytic system for use in the process according tothe invention is formed from quinoline and orthophosphoric acid in aweakly basic solvent (i.e., dioxane). This is obtained by reaction ofsubstantially one molar equivalent of quinoline and two molarequivalents of orthophosphoric acid.

The process according to the invention is preferably carried out in aweakly basic organic solvent to regulate acidity, homogeniety andtemperature. Ordinarily, the penicillanic acid sulfoxide will be in asolution in the organic solvent. The solvent should be substantiallyinert to the penicillanic acid sulfoxide used in the process and to the3-methylceph-3-em-4-carboxylic acid produced by the process.

Solvents which may be used include those described in US. Pat. No.3,275,626 and other publications describing the rearrangement reaction.However, particu- 'larly suitable solvents include ketones boiling atfrom -l20 C. (e.g., l00-l20 C.), esters boiling at from 75l40 C. (e.g.,lO0-l30 C.), dioxane and diethylene glycol dimethyl ether (diglyme).illustrative of those ketones and esters that may be used in the processaccording to the invention are aliphatic ketones and esters havingappropriate boiling points including ethyl methyl ketone, isobutylmethyl ketone, methyl n-propyl ketone, n-propyl acetate, n-butylacetate, isobutyl acetate, sec-butyl acetate and diethyl carbonate.These solvents are capable of being protonated by a strong acid and assuch are considered weakly basic organic solvents."

The time for achieving optimum yields by the process according to theinvention varies according to the particular solvent and temperatureemployed. The rearrangements are conveniently carried out at the boilingpoint of the chosen solvent and, for those solvents boiling in the lowerpart of the ranges quoted above, correspondingly longer reaction times,e.g., up to 48 hours, may be required than for those solvent boiling athigher temperatures. For example, rearrangements in dioxane generallyrequire times of 7-15 hours to achieve optimum results whereas thosecarried out in methyl isobutyl ketone generally require times of 1-8hours. The

yields in the rearrangements are dependent, but to a lesser extent, onthe concentration of the catalyst in the solvent, correspondingly longerreaction times being required for lower concentrations of catalyst.

We particularly prefer to use dioxane as the organic solventsincepenicillanic acid sulfoxides can be dissolved in this solvent in highconcentration and in general there is no falling off of yield withincrease of concentration up to concentrations of the order of 35percent.

The quantity of the strong acid used in the rearrangement should notgenerally exceed 1.0 mole per mole of the penicillanic acid sulfoxide,however, we generally prefer to use it in proportions of from 0.05 to0.5 mole per mole of penicillanic acid sulfoxide.

The quantity of the nitrogenous base used in the rearrangement shouldnot generally exceed 1.0 mole per mole of the penicillanic acidsulfoxide; however, we generally prefer to use it in proportions of from0.025 to 0.25 mole per mole of penicillanic acid sulfoxide.

The appropriate time interval for any particular reaction may bedetermined by testing the reaction solution by one of more of thefollowing procedures:

1. Thin layer chromatography, for example on silica gel, developing with321:1 n-butanolacetic acid water system and rendering the spots visibleby treatment with a sulfuric acid spray.

2. Determination of the rotation after suitable dilution of the reactionmixture with, for example,

chloroform.

3. Determination of the ultraviolet spectrum of a sample of the reactionmixture suitably diluted with ethyl alcohol. This determination cannotbe adapted when ketonic solvents are used as the reaction media.

4. NMR (nuclear magnetic resonance).

Although satisfactory yields can be obtained by carrying out thereaction under normal reflux, it may be possible to improve the yieldsby inserting a desiccating agent (e.g., alumina, calcium oxide, sodiumhydroxide or molecular sieves) which is inert to the solvent in thereflux return line to remove water formed during the reaction.Alternatively, the water formed during the reaction may be removed bythe use of a fractionating column the water formed being removed byfractional distillation.

After completion of the reaction the salt may be removed either beforeor after concentrating the reaction mixture. If the reaction solvent isimmiscible with water, the complex can be removed by a simple washingprocedure. On the other hand, if the reaction medium is miscible withwater a convenient purification technique is to remove the reactionsolvent (this may be achieved by distillation under reduced pressure)and then to purify the residue by a convenient process, e.g.,chromatography on silica gel, etc., or precipitation by salt formation,fractional crystallization, etc.

It has been found that the degree of conversion achieved by the processaccording to the invention may be such that complicated purificationprocedures can be dispensed with and the product isolated in asubstantially pure condition after a simple crystallization process.

The product may be isolated by pouring the reaction mixture into water,filtering off the product and, if desired, further purifying byrecrystallization from, or slurrying with, a suitable solvent.

The penicillanic acid sulfoxide used as the starting material in therearrangement process according to the invention is derived from afermentable penicillin or a salt thereof. The preferred penicillins usedin this process are 6-phenylacetamidopenicillanic acid and 6-phenoxyacetamidopenicillanic acid or a salt thereof.

The oxidation may be carried out as described by Chow, Hall and Hoover(J. Org. Chem. 1962, 27, 1,381). The penicillin is mixed with theoxidizing agent in an amount such that at least one atom of activeoxygen is present per atom of thiazolidine sulphur. Suitable oxidizingagents include hydrogen peroxide, metaperiodic acid, peracetic acid,monoperphthalic acid, mchloroperbenzoic acid and t-butyl hypochlorite,the latter being preferably used in admixture with a weak base, e.g.,pyridine. An excess oxidizing agent may lead to the formation ofl,l-dioxide. The l-oxide may be obtained in the R- and/or S-form.

Acyl groups at the 6-amino position of the penicillanic and sulfoxidemay be any desired acyl group but should preferably be reasonably stableunder the conditions of the rearrangement. Conveniently, the acyl groupat the 6-position is that of a penicillin obtained by a fermentationprocess, e.g., phenylacetyl or phenoxyacetyl. Such a group may not bethe desired group in the cephalosporin end-product but this can beobviated by subsequent transformations described below. Another acylgroup which may conveniently be used is the formyl group.

Alternatively, the acyl group at the 6-position of the penicillanic acidsulfoxide may be that desired in the cephalosporin compound.

Where the product of the rearrangement is a 7-acylamidoceph-3-em-4-carboxylic acid not having the desired acyl group,the 7-acylamido compound may be N-deacylated, if desired after reactionselsewhere in the molecule, to yield the corresponding 7-amino compoundand the latter then acylated with an appropriate acylating reagent.

Methods'of N-deacylating cephalosporin derivatives having 7-acylamidogroups are known and one suitable method comprises treating a7-acylamidoceph-3-em-4- carboxylic acid ester with an imide halideforming component, converting the imide halide so obtained into theimino ether and decomposing the latter. lf desired, the ester group maybe split off by hydrolysis or hydrogenolysis to yield the 4-carboxylicacid.

Suitable imide halide forming components include acid halides derivedfrom phosphorous, the preferred compounds being the chlorides such as,for example, phosphorus oxychloride or phosphorus pentachloride.

This method of N-deacylation is described in greater detail in BelgianPat. No. 719,712. N-Deformylation of a 7-formamido group may be effectedwith a mineral acid at a temperature of l5 to C., preferably +l5 to 40C. A convenient reagent for the N- deformylation is concentratedhydrochloric acid in methanol or, preferably, in dioxane ortetrahydrofuran since undesired transesterification reactions that tendto occur in methanol are thereby avoided. A most preferred deacylationprocess is described in U.S. Pat. No. 3,499,909 (see example 7 herein).

Applicants have found much to their surprise, that despite the teachingsof the prior art, it is possible and practical to rearrange penicillanicacid sulfoxides to 3- methylceph-3-em-4-carboxylic acids with littledecarboxylation occurring. This discovery offers a multitude ofadvantages over the process of rearranging the penicillanic acidsulfoxide esters in that it avoids the necessity of first esterifyingsaid penicillanic acid or penicillanic acid sulfoxide and subsequent tothe rearrangement, de-esterifying said 3-methylceph-3-em-4- carboxylateester.

A preferred embodiment of the present invention is the process for thepreparation of a compound having the formula in which R is the sidechain of a penicillin produced by fermentation and M is H or a cation;which process comprises heating a compound having the formula in which Rand M are as above; in a weakly basic organic solvent in the presence ofa catalyst of a strong acid and a nitrogen base, said base having a pKbof not less than 4, or a strong acid alone, with the aid of heat.

Another preferred embodiment is the process for the preparation of acompound having the formula H s, a-carin which R is hexyl,thiophene-Z-methyl, phenylmethyl, phenyl, phenoxymethyl,phenylmercaptomethyl, said phenyl group having the formula in which R isH, Cl, CH CH O or N0 and M is hydrogen, sodium, potassium, calcium,aluminum, lithium, a cation derived from a tri-(lower)alkylamine,pyridine, benzylamine, or a N-(lower)alkylpiperidine; which processcomprises heating a compound having the formula 2 H H v s 5, R-C'-N-- 3o Nm- (10 M in which R and M are as above, in a weakly basic solventwith a catalytic amount of a strong acid and a nitrogen base, said basehaving a pKb of not less than 4.

Another preferred embodiment is the process for the preparation of acompound having the formula in which R is hexyl, thiophene-Z-methyl,phenylmethyl,

phenyl, phenoxymethyl, phenylmercaptomethyl, said phenyl group havingthe formula in which R is H, Cl, CH CH O or N0 and M is hydrogen,sodium, potassium, calcium, aluminum, lithium, a cation derived from atrialkylamine, pyridine, benzylamine, or a N-(lower)alkylpiperidine;which process comprises heating a compound having the formula in which Rand M are as above, in a weakly basic solvent with a catalytic amount ofa strong acid and a nitrogen base, said base having a pKb of ot lessthan 7.

A more preferred embodiment is the process for the preparation of acompound having the formula in which R is hexyl, thiophene-Z-methyl,phenylmethyl,

phenyl, phenoxymethyl, phenylmercaptomethyl, said phenyl group havingthe formula in which R is'l-l, Cl, CH CH O or N which process comprisesheating a compound having the formula in which R is as defined as above,in a weakly basic organic solvent selected from the group comprisingdioxane, tetrahydrofuran, ethyl methyl ketone, isobutyl ketone, methyln-propyl ketone, n-propyl acetate, n-butyl acetate, isobutyl acetate,sec-butyl acetate, diethyl carbonate, or diethylene glycol dimethylether, at a temperature range of about 50 C. to about the refluxtemperature of the solvent system, for a period of time of up to about48 hours, said time partially determined by the temperature at which theprocess is conducted, in the presence of a catalytic amount ofpyridinedi(phosphoric acid) complex.

A still more preferred embodiment is the process for the preparation ofa compound having theformula g CH CH CO H II in which R is as above; ina'weakly basic organic solvent selected from the group comprisingdioxane, tetrahydrofuran, ethyl methyl ketone, isobutyl acetate,secbutyl acetate, diethyl carbonate, or diethylene butyl acetate,sec-butyl acetate, diethyl carbonate, or diethylene glycol dimethylether, at a temperature range of about 50 C. to about the refluxtemperature of the solvent system, for a period of time of up to about48 hours, said time partially determined by the temperature at which theprocess is conducted, in the presence of pyridine-di(phosphoric acid)complex, said complex being present in a molar ratio of about 0.05 to0.5 moles per mole of compound ll.

A most preferred embodiment is the process for the preparation of acompound having the formula in which R is benzyl or phenoxymethyl; whichprocess comprises heating a compound having the formula in which R is asabove; in dioxane at reflux temperature for a period of about 4 to about12 hours, in the presence of pyridine-di(phosphoric acid) complex, saidcomplex being present in a molar ratio of about 0.05 to 0.2 moles permole of compound ll.

The 3-methylceph-3-em-4-carboxylic acids (l) produced by the instantinvention can be readily converted to 7-ADCA according to the processdescribed in US. Pat. No. 3,499,909 in excellent yield (see column 7,example 4), for example:

2.23 g. of the N-ethyl-piperidine salt of N-phenacetyl-3desacetoxy-7aminocephalosporanic acid were suspended in 18ml. of methylene chloride, and after addition of 1.3 ml. ofdimethylaniline, 1 ml. of trimethylchlorosilane was added thereto toform the corresponding trimethylsilyl ester. After 1 hour, the mixturewas cooled to 50 C. and 1.1 g. of PCI was added. For 2% hours thetemperature was held at 40 C. and then lowered to 65 C. A solution of0.3 ml. of dimethylaniline and 12 ml. of butanol was added to the cooledmixture and then the temperature was held for 2% hours at 40 C. Thereaction mixture was poured into a mixture of 35 ml. of water and 17 ml.of methanol, and brought at once to a pH of 3.5 with the aid of ammoniumbicarbonate. After about 20 hours storage at 5 C., the precipitate wasfiltered off, washed with methanol-water l:l), methylene chloride andacetone, and dried to obtain 0.936 gm. (92 percent yield) ofdesacetoxy-7aminocephalosporanic acid.

The 7-ADCA so isolated can then be acylated to produce antibacterialcephalosporin compounds, for example:

7-( D-a-aminophenylacetamido )-3-methyl-A- cephem-4-carboxylic acid,

7-( dl-a-amino-m-chlorophenylacetamido )-3-methylcephem-4-carboxylicacid, 7-(dl-a-amino-p-chlorophenylacetamido)-3-methyl- A-cephem-4carboxylic acid,7-(d1-a-amino-p-chlorophenylacetamido)-3-methyl- A -cephem-4-carboxylicacid trifluoroacetate, 7-(dl-a-amino-m-bromophenylacetamido)-3-methyl- A-cephem-4-carboxylic acid,7-(dl-a-amino-m-bromophenylacetamido)-3-methyl- A -cephem-4-carboxylicacid trifluoroacetate,

7-(dl-a-amaino-m-fluorophenylacetamido)-3- methyl-A -cephem-4-carboxylicacid, 7-(dI-a-amino-m-methoxyphenylacetamido)-3- methy1-A-cephem-4-carboxy1ic. acid, 7-(d1-a-amino-m-methoxyphenylacetamido)3-methyl-A -cephem-4-carboxy1ic acid,7-(dl-a-amino-m-methoxyphenylacetamido)-3- methyl-A -cephem-4-carboxylicacid trifluoroacetate, 7-(D-a-amino-m-hydroxyphenylacetamido)-3-methyl-A -cephem-4-carboxylic acid,7-(p-chlorophenoxyacetamido)-3-methyl-A cephem-4-carboxylic acidpotassium salt, 7-(m-nitrophenoxyacetamido)-3-methyl-A -cephem-4-carboxylic acid potassium salt,7-phenylmercaptoacetamido-3-methy1-A-cephem-4- carboxylic acid potassiumsalt, 7-(n-butylmercaptoacetamido)-3-methyl-A cephem-4 carboxylic acidpotassium salt, and 7-(m-chlorophenylmercaptoacetamido)-3-methyl- A-cephem-4-carboxylic acid potassium salt. For the purpose of thisdisclosure, the term (lower) 1 alkyl is herein defined as an alkyl groupcomprised of from 1 to 8 carbons, said moiety being a straight orbranched chain, saturated or monounsaturated hydrocarbon chain.

It is also to be understood for the purpose of this application thatthis process can be run at elevated pressures. As such, lower boilingsolvents can be employed at temperatures above their boiling points. Forexample, if the reaction is conducted in a closed vessel, the processemploying tetrahydrofuran could be conducted at 150 C. if so desireddespite the fact that this temperature is above the reflux temperatureof tetrahydrofuran at atmospheric pressure. The invention is meant toalso embody said reaction conditions using elevated pressures.

EXAMPLE 1 Preparation of 7-(Phenoxyacetamido)desacetoxycephalosporanicAcid (2) by Rearrangement of Penicillin V Acid Sulfoxide (1) Thepyridine-di(phosphoric acid) complex (PDPA) was prepared as follows:Pyridine (7.9 g., 0.10 mole) was added in portions to a stirred andice-cooled solution of 85 percent orthosphosphoric acid (23.0 g., 0.20mole) in 100ml. of tetrahydrofuran. The white solid precipitate wascollected by filtration, washed with THF and ether and dried in vacuoover P yield: 25.4 g. (92 percent).

A mixture of penicillin V sulfoxide (18.3 g., 0.050 mole), PDPA (1.38g., 0.005 mole) and anhydrous dioxane (300 ml.) was heated under reflux(oil bath) for 8 hours. The refluxing dioxane was passed through Linde4A molecular sieves (-100 g.) in a Soxhlet apparatus before returning tothe flask. The solvent was removed under reduced pressure and theresidue treated with a mixture of ethyl acetate (200 ml.) and water (50ml.). The ethyl acetate layer was extracted with l N aqueous sodiumbicarbonate (-m1.). The bicarbonate extract was cooled and acidifiedwith dilute hydrochloric acid. The semi-solid precipitate was extractedinto ethyl acetate( 125 ml.). This solution was dried (MgSOQ andconcentrated to dryness giving 14.0 g. of a yellow solid foam. By n.m.r.spectroscopy, using o-toluic acid as an internal standard, the amount ofthe desired product was estimated at 6.30 g. (36 percent). To a coldsolution of the crude product in 25 ml. of methanol was addeddibenzylamine (7.9 g., 0.040 mole). After the addition of some seedcrystals the dibenzylamine salt of 2 crystallized readily. After coolingovernight at 15, the solid was collected by filtration and washedsuccessively with cold methanol and ether. There was obtained 7.5 g. (28percent) of white fluffy solid, mp. l35-136 (dec.). The infraredspectrum of this salt was superimposable with that of the dibenzylaminesalt of authentic 2 (mp. 141-l42 (dec.), after recrystallization frommethanol).

The dibenzylamine salt was briefly shaken with ml. of ethyl acetate and30 ml. of l N hydrochloric acid. Dibenzylamine hydrochloridecrystallized from this mixture and was collected by filtration and dried(2.5 g., 78 percent). The ethyl acetate layer was dried (MgSO andconcentrated to a volume of approximately 20 ml. A white solidcrystallized readily and, after cooling, was collected by filtration;yield: 4.1 g. (24 percent), m.p. 173l75 (dec.); -y,,,,, 3450 (NH), 1760(B-Iactam carbonyl), 1730 (amide carbonyl) and 1670 cm (carboxyl). Theinfrared and n.m.r. spectra were superimposable with those of anauthentic sample of 2, mp. l77l 78 (dec. prepared from phenoxyacetylchloride and 7- aminodesacetoxycephalosporanic acid.

EXAMPLE 2 Rearrangement of Penicillin V Acid Sulfoxide (1) to7-(Phenoxyacetamido)desacetoxycephalosporanic Acid (2) Under VariousConditions.

The essence of Example 1 was repeated using variable conditions such as(1 differing proportions of the sulfoxide and acid catalyst; (2)different solvents; (3) different reaction times; (4) with or without adesiccant; and (5) differing reaction temperatures to obtain the resultsreported below:

7-(PHENOXYACETAMIDOiDESACETOXYCEPHALOSPORANIC ACID BY REARRANGEMENT OFPENICILLIN V SULFOXIDE YIELD OF 2 REAC- REAC- ACTUAL ISOLATED ASISOLATED EXP. MMOLES CATALYST TION ON (FROM (MHONH 5 PURE NO. OF 1 (MOLEEQUIV.) DESICCANT SOLVENT TEMP. TIME N.M.R.) SALT CRYST.)

I 10 DDP (0.05) M01. dioxane reflux 3 14 9 2 do. do. (0.2) do. 3 21 15 3do. do. (0.1) do. 1 9 6 4 do. do. (0.1) do. 2 15 9 5 do. do. (0.1) do. 3I7 11 6 do. do. (0.1 do. 4 18 I5 7 do. do. (0.1) do. 5,. 22 17 8 do. do.(0.1) do. 3 14 7 9 50 do. (0.1) do. 4 21 17 14 10 do. do. (0.1) MIBK 321 23 17 11 10 MDP (0.1) dioxane 3 24 l4 12 do. do. (0.1) do. 5 22 18 13do. do. (0.1) MIBK 3,, 15 11 14 do. do. (0.1) dioxane 5,. 19 137-(PHENOXYACETAMIDO)DESACETOXYCEPHALOSPORANlC ACI D BY REARRANGEMENT OFPENlClLLlN V SULFOXIDE- Continued YIELD OF 2 REAC. REAC. ACTUAL ISOLATEDAS ISOLATED EXP. MMOLES CATALYST TlON TlON (FROM b zlz PURE NO. OF 1(MOLE EQUlV.) DESlCCANT SOLVENT TEMP. TIME N.M.R.) SALT CRYST.)

. 15 do. MDP(0.1)+

TMO'"(2.0) do. 5 l3 9 16 50 MDP (0.1) do. 4' 23 22 17 17 pyr.(0.1) do. 43.5 1 18 do. pyr. TsOH (0.1) do. 3 7 5.5 l9 l0 pyr. H=PO (0.1) do. 3 106 20 do. pyr H PO do.

(0.1 d0. 8 23 13 2| l0 PDPA (0.1) do. 8 28 23 22 50 PDPA (0.1) do. 8 3628 24 23 10 H,PO (0.1) do. 8 12 8 24 2.7 none I do. 4 0 25 1O PDPA M01.sieves dioxane" reflux 2 12 10 26 10 do. 0. do. do. 4 25 19 27 50 do.none do. do. 8 22.5 20 28 10 do. Ac o do. do. 4 25 19.5 29 50 do. Ac Odo. do. 6 27.5 22 30 50 do. Ac,0 do. do. 8 26 23.5 18 31 10 do. Ac O do.do. 8 22 20.5 32 10 do. none do. 130-35 1 20 14.5 33 10 do. Ac O do.130-35 1 21 17 34 10 do. A'c,0 diglyme l0510 2.5 23 20 35 50 do. nonedo. l10l5 2 19.5 17 36 10 do. Ac o do. 125-30 1 27 25 37 10 do. A,o do.125-30 1 18 12.5 38 10 do. none do. 125-30 1 22.5 14.5 39 10 do. A0 0do. 135* 1 14 11.5 40 10 do. none do. 135 2 1 30 15.5 41 10 do. Ac o do.140-45 0.5 23 23 42 10 pyr. H PO Mol. sieves dioxane reflux 5 10 7 43 50H,PO none do. do. 16 l5 15 6.5 44 10 HJO, Mol. sieves do. do. 4 2 2 4510 pyr. oxalic acid mol. sieves do. do. 8 3 3 46 10 pyr. o-NO,oOO,H mol.sieves do. do. 4 2 1.5 47 10 p-NH'SO,H none do. do. 16 5 48 10 PDPA noneDMF IDS-10 2.25 3 49 10 PDPA none THF reflux 5O 50 PDPA none MlBK do. 3l0 10 51 10 PDAC MgSO dioxane do. 4 8 5 52 l0 PDAC B 0: do. do. 4 5 3 53I0 PDPA CuSO do. do. 4 54 10 N(CH ),.2H;,PO mol. sieves do. do. l0 16 ll55 10 NH,2H,PO mol. sieves do. do. 8 15 9 56 10 Et,N.2H;,PO mol. 'evesdo. do. 6 2 2 57 10 2-picoline.

2H PO mol. sieves do. do. 8 12.5 9.5 58 10 4-picoline.

- ZH PO, mol. sieves dioxane reflux 5 19.5 14 59 10 quinoline.

ZHJO, mol. sieves do. do. 8 26 19.5 60 10 quinoline.

ZH PO Ac O do. do. 8 21 18.5 61 50 I quinoline.

2H;,PO None do. do. 8 25 23 20 62 10 isoquinoline.

21-1,,PO Ac O do. do. 8 20.5 14 63 100 PDPA none do. do. 8 20 I8 PDPA:pyridine-di(phosphoric acid) complex; 0.1 mole equivalent of catalystwas used in all experiments. "In the experiments with molecular sieves(Linde 4A; -2 g. per m.mole of sull'nxitfe) the desiccant was placed ina Soxhlet; the other drying agents (2 mole equivalents) were part of thereaction mixture. 0.17 Molar solutions were employed, except Exp. 63which was 0.20 molar.

'No desiccant.

'TMO=Trimethyl Orthoformate. Pyridine-di(phosphoric acid) (PDPA)Monopyridinium Dichloromcthylphosphonate (MDP) DipyridiniumDichloromethylphosphonatc (DDP) Pyridinium p-toluenesulfonatc (PYR,TsOH) Pyridine (PYR) EXAMPLE 3 Rearrangement of 1 Into 2.

A mixture of penicillinV sulfoxide (1'8.3 g. 0.050

mole), PDPA (1.38 g., 0.005 mole) and dioxane 300 lution of this in 25ml. of methanol was cooled and treated with dibenzylamine (7.9 g. 0.040mole). After cooling at l5 overnight the white solid precipitate wasfiltered off and washed with cold methanol and ether. The dibenzylaminesalt of the cephalosporanic acid amounted to 6.1 g. (22.5 percent), m.p.l37-l 38 (dec.). To liberate the eephalosporanic acid it was brieflyshaken with a mixture of ethyl acetate ml.) and l N hydrochloric acid(30 ml.). The precipitated dibenzylamine hydrochloride (2.14 g., 82percent) was removed by filtration. The ethyl acetate solution was dried(MgSO and concentrated to a volume of 15-20 ml. A white solidcrystallized readily and, after cooling. was collected by filtration;yield: 3.45 g. (20 percent) desacetoxycephalosporanic of7-(phenoxyacetamido)desacetoxycephalosporanic acid, m.p. 172-173 (dec.).

EXAMPLE 4 Rearrangement of 1 Into 2 A mixture of penicillin V sulfoxide(18.3 g., 0.050 mole), PDPA (1.38 g., 0.005 mole) and bis(2-methoxyethyl) ether (diglyme; 300 ml.) was stirred at 1l0-115 for 2hours. The reaction mixture was worked-up as in Experiment 3 to give4.75 g. (17 percent) of the dibenzylamine salt, m.p. 130-134 (dec.),from which 1.75 g. percent) of 7-(phenoxyacetamido)desocetoxycephalosporanic acid, m.p. l68-70 (dec.),was isolated.

EXAMPLE 5 Rearrangement of 1 Into 2 A mixture of penicillin V sulfoxide(18.3 g., 0.050 mole), quinoline (0.65 g., 0.0050 mole), 85 percentorthophosphoric acid (0.98 g., 0.0085 mole) and dioxane (300 ml.) washeated under reflux for 8 hours. The reaction mixture was worked-up asin Experiment 3 to give 6.3 g. (23 percent) of the dibenzylamine salt,m.p. 135l36 (dec.), from which 3.5 g. percent) of 7-(phenoxyacetamido)desacetoxycephalosporanic acid, m.p. 174175 (dec.) wasisolated.

EXAMPLE 7 Preparation of 7aminodesacetoxycephalosporanic acid(7-amino-3-methylceph-3-em-4-carboxylic acid) (3) from7-(phenoxyacetamido)desacetoxycephalos poranic acid(7-phenoxyacetamido)-3-methylceph-3- em-4-carboxylic acid) (2)- Asolution of trimethylchlorosilane (0.65 g., 6.0 mmole) in 5 ml. of CH C1was added dropwise in 3.5 minutes to a stirred mixture of 2 (1.74 g.,5.0 mmole), triethylamine (0.50 g., 5.0 mmole) and N,N- dimethylaniline(1.2 g., 10.0 mmole) in ml. of CH Cl at room temperature with stirring.The mixture was stirred an additional 30 minutes and then cooled to 55C. Phosphorous pentachloride (1.15 g., 5.5 mmole) was added and thetemperature maintained at stirring for 2 hours, then cooled again to 60C. and 15 ml. of methyl alcohol and 0.3 g. of dimethy1aniline was addedrapidly in 3 minutes (temperature rose to 50 C The resultant mixture wasstirred at 40 i 4 C. for 2 hours and poured into an ice cold mixture ofwater (25 ml.) and methanol (12 ml.) with stirring. The pH of thestirred mixture was adjusted to 3.5 (initially l) with ammoniumcarbonate The mixture was cooled under refrigeration for 18 hot'irs andthe solid precipitate was collected by filtration. The solid was washedwith 15 ml. portions of ice water (2X) methanol (2X) and ether. Thesolid was dried in vacuo over P 0 to yield 0.83 g. (78 percent) of whitecrystalline solid that was determined to be identical with authentic 3.

EXAMPLE 8 Preparation of 7-(2,2-Dimethy1-4-oxo-4-phenyl-1-imidazolidinyl)3 methylceph-3em-4-carboxylic acid Place 0.10 mole of7-ADCA in 300 ml. of anhydrous methylene chloride at 0l0 C. Add 28.0 ml.(0.204 ml.) of triethylamine and 15.0 ml. (0.118 mole) ofdimethylaniline. Slowly add 25.4 ml. (0.2 mole) of trimethylchlorosilanewhile keeping the temperature at -10 C. Reflux the mixture for 30minutes at 43 C. or stir for 2 hours at 510 C. Cool the mixture to 05 C.and slowly add 0.1 mole of phenylglycine chloride hydrochloride withstirring. Agetate for 1.5 to 2 hours at 05 C.

Add 30 ml. of triethylamine to the anhydrous acylation mixture.Immediatelv add ml. of acetone (chilled to 05 C.) followed by 300 ml. of0-5 C. water. Agetate for 15 minutes and bring the pH into the range of7.5 to 8.5 with 6N HCl or triethylamine if not in this range. Filterthrough filter aid and wash the cake with 75 ml. of cold water and 75ml. of methylene chloride. Add the washer to the filtrate.

Separate the filtrates. Add to the water phase an additional ml. ofmethylene chloride. Stir five minutes and separate. Add 300 ml. ofacetone to the aqueous phase and adjust the pH to 8.5-8.9 with 10percent sodium hydroxide. Cool the reaction mixture for 16-20 hours at05 C. Collect the resultant crystals which are determined to be7-(2,2-dimethy1-5-oxo-4-phenyl-1imidazolidinyl)-3methylceph-3-em-4-carboxylic acid.

EXAMPLE 9 Preparation of 7-(D-a-aminophenyacetamido)-3-methylceph-3-em-4-carboxylic acid V Suspend 10 gm. of7-(2,2-dimethyl-5oxo-4-phenyll-imidazolidiny1)-3-methylceph-3em-4-carboxylicacid in about 0.75 ml. of water with rapid stirring at room temperature.Slowly add 1020 mole percent of 10 percent sodium hydroxide (based onthe 10 gm. of cephem compound used) and continue to stir. The solid 7-(2,2-dimethyl-5-oxo-4-phenyl- 1imidazolidinyl)-3methylceph-3em-4-carboxylic acid slowly dissolves inthe system and subsequently 7-( D-aaminophenylacetamido)3-methylceph-3-em-4- carboxylic acid proceeds to crystallize. [f the pHrises, the pH is adjusted to pH 5.5-7. As a final pH, the mixture shouldbe adjusted to pH 304 to obtain the maximum yield of material identifiedto be authentic V.

We claim:

1. The process for the preparation of a compound having the formula inwhich R is hexyl, thiophene-Z-methyl, phenylmethyl, phenyl,phenoxymethyl, phenylmercaptomethyl, said phenyl group having theformula in which R is H, Cl, CH CH O or N0 which process Comprises v 1.aHa an ews! y nathrcwfor a h 82H II in which R is as defined as above, ina weakly basic organic solvent selected from the group comprised ofdioxane, tetrahydrofuran, ethyl methyl ketone, isobutyl ketone, methyln-propyl ketone, n-propylacetate, nbutyl acetate, isobutyl acetate,sec-butyl acetate, diethyl carbonate and diethylene glycol dimethylether, at a temperature range in the range of about 50 C to about thereflux temperature of the solvent system, for a period of time of up toabout 48 hours, said time partially determined by the temperature atwhich the process is conducted, in the presence of a catalytic amount ofpyridine-di-(phosphoric acid) complex, said complex being present in amolar ratio of about 0.05 to 0.5

moles per mole of compound II.

1. THE PROCESS FOR THE PREPARATION OF A COMPOUND HAVING THE FORMULA